The Israeli leader took off around midday accompanied by six of his ministers, including his newly reappointed foreign minister Avigdor Lieberman, public radio said.
During the visit, Netanyahu is also due to meet his Italian counterpart Enrico Letta, and will hold a joint session with the Italian cabinet, it said.
On Monday, he will be granted his first audience with Pope Francis, who took over as the worldwide head of the Catholic Church in March.
Six weeks ago, Netanyahu's office had said he would meet the pope during a visit to Rome in late October, but the meeting never happened — with a diplomatic source telling AFP it would not happen because it had not been coordinated in advance with the Vatican.
When the two meet on Monday, they are likely to discuss the Iranian nuclear issue and the ongoing peace talks with the Palestinians.
And they are also expected to discuss the pope's planned visit to the Holy Land early next year.
Pope Francis has already been invited to visit the Christian holy sites by Israeli President Shimon Peres in April, and by Palestinian leader Mahmud Abbas, who met him on October 17.
Israeli sources say the visit could take place before Peres ends his term as president in July. Although no date has been made official, sources on both sides say it is likely to take place on May 25-26.
The papal visit will reportedly begin in Jordan, a senior Vatican official said on Saturday, according to Jordanian state news agency Petra.
"The pope's visit to the Holy Land will begin in Jordan," Vatican foreign affairs official Dominique Mamberti said in Amman after meeting Jordan's Foreign Minister Nasser Judeh.
Israel and the Vatican first established full diplomatic relations in 1993, but have been engaged in years of thorny diplomatic negotiations over property rights and tax exemptions for the Catholic Church, which have yet to be fully resolved.
The Holy See wants full recognition of the legal and patrimonial rights of Catholic communities in Israel and formal confirmation of tax exemptions enjoyed by the Church since the Jewish state's emergence in 1948 and which the UN has asked Israel to honour.
One of the most delicate questions involves access by Catholic worshippers to a site on Mount Zion in Jerusalem called the Cenacle, where Christians believe Jesus held the Last Supper the night before he was crucified.
In June, the sides agreed to step up negotiations over the outstanding issues.